Infections of the Urinary Tract (UTI) are extremely common. UTIs are the second most common reason for physician visits, and account for about 8.3 million doctor visits each year. (Ambulatory Care Visits to Physician Offices, Hospital Outpatient Departments, and Emergency Departments: United States, 1999/2000. Vital and Health Statistics. Series 13, No. 157. Hyattsville, Md.: National Center for Health Statistics, Centers for Disease Control and Prevention, U.S. Dept. of Health and Human Services; September 2004.) Men, women and children develop UTIs. Evidence indicates that urinary tract infections are due to enterobacteria, principally Escherichia coli. 
Symptoms of UTI include a frequent urge to urinate and a painful, burning feeling in the area of the bladder or urethra during urination. It is not unusual to feel bad all over—tired, shaky, washed out—and to feel pain even when not urinating. Often women feel an uncomfortable pressure above the pubic bone, and some men experience fullness in the rectum. It is common for a person with a urinary infection to complain that, despite the urge to urinate, only a small amount of urine is passed. The urine itself may look milky or cloudy, even reddish if blood is present. Normally, a UTI does not cause fever if it is in the bladder or urethra. A fever may mean that the infection has reached the kidneys. Other symptoms of a kidney infection include pain in the back or side below the ribs, nausea, or vomiting.
UTIs usually occur when bacteria enter the opening of the urethra and multiply in the urinary tract. The urinary tract includes the two kidneys, ureters (tubes that carry urine from the kidneys to the bladder), the bladder itself, and the urethra (the tube that carries urine from the bladder to the urethral opening). A UTI limited to the urethra is called urethritis. If the infection migrates to the bladder it is called cystitis. If the infection migrates to the kidneys it is called pyelonephritis. Infections of any and all urinary tract components as described are considered UTI herein and the methods of the present invention are effective treatments and preventions for each and all.
Women are more prone to UTIs than men, probably because they have shorter urethras, which therefore pass bacteria into the urinary tract more easily. Statistics show that one in every five women will develop a UTI during her lifetime. Although the estimated prevalence of UTI varies, all reports indicate a staggering number of female UTI sufferers: 7 to 11 million women, or 7 to 11 percent of adult women in the U.S., visit their physicians for a UTI each year. Overall 20 to 60 percent of women will have at least one UTI over their lifetime. After having one UTI, up to 20 to 30 percent will suffer from recurrent infections. Sexually-active women are especially prone to UTIs and recurrent UTIs (Foxman, B., et al. 2000. Ann. Epidemiol. 10:509-15; Foxman, B. 1990. Am. J. Pub. Health, 80:331-333; Manges et al. 2001. NEJM, 345:1007-1013; Sotelo T M, and Westney O L, 2004. Women's Healthcare, 2004, 2-6). Women who have had more than three UTIs are likely to continue to develop recurrences within 18 months of a UTI. In severe cases this can be even more frequent.
Urinary tract infections most commonly occur in the bladder (cystitis, or “honeymoon disease”), and uncomplicated UTI is usually caused by strains of Escherichia coli (E. coli). In healthy women with uncomplicated cystitis, the usual treatment includes three days of antibiotics. The typical drugs chosen are: trimethoprim (Trimpex®), trimethoprim-sulfamethoxazole (Bactrim DS® by Roche, Septra, Cotrim), amoxicillin (Amoxil, Trimox, Wymox), nitrofurantoin (Macrobid® by Proctor and Gamble, Furadantin), ampicillin (Omnipen, Polycililin, Principen, Totacillin), ofloxacin (Floxin), norfloxacin ((Noroxin), ciprofloxacin (Cipro® by Bayer), trovafloxin (Trovan) and levofloxacin (Levaquin® by Ortho-McNeil). Recurrent UTIs can be treated with a low dose of antibiotics following intercourse, or by taking daily or thrice-weekly antibiotics for six months to several years (Stamm and Hooten, 1993. NEJM 329:1328). Clinical management of UTI is complicated by the increasing incidence of infections caused by E. coli that are resistant to commonly used antibiotics (especially trimethoprim-sulfamethoxazole). In recent studies, 15 to 22 percent of UTI cases were antibiotic resistant (Manges, supra; Gupta et al., 1999. JAMA 281:736-8). Furthermore, frequent use of antibiotics will also affect immune system functioning. A healthy immune system is important in the prevention of UTI. This means that antibiotics used to cure UTI may make another infection more likely in the near future. So-called “alternative remedies have also be suggested (See, e.g. Stevenot, U.S. Pat. No. 6,143,300)
There is some suggestion that one factor behind recurrent UTIs may be the ability of bacteria to attach to cells lining the urinary tract. A recent NIH-funded study found that bacteria formed a protective film on the inner lining of the bladder in mice. Another line of research has indicated that women who are “non-secretors” of certain blood group antigens may be more prone to recurrent UTIs because the cells lining the vagina and urethra may allow bacteria to attach more easily. (http://kidney.niddk.nih.gov/kudiseases/pubs/utiadult/)
Men are not as prone to UTIs as women, but infections are still common. The prostate gland in men produces secretions that retard the growth of bacteria. While men develop UTIs less frequently than women, their infections tend to be more severe. UTIs in men are often caused by an obstruction (e.g. a urinary stone) or an enlarged prostate. Prostate-related UTIs are more difficult to cure via conventional means because many antibiotics do not easily penetrate infected prostate tissue.
The outer cell walls of yeast are comprised entirely of mannose and N-acetyl glucosamine (as the disaccharide chitobiose), these sugars being linked to proteins to form a coat of glycopeptides. Mannose is the predominant sugar, hence the outermost layer of the cell wall of yeast may be said to consist of mannoproteins; and the carbohydrate part of these mannoproteins is generally called “mannan”. A molecule of mannan may be comprised of hundreds if not thousands of mannose molecules, all linked together in chains and branches of chains. The covalent mannose-mannose bonds found in yeast mannan are primarily in the alpha configuration, the exception being the mannose to chitobiose beta linkage, where the N-linked mannan is anchored to protein of the cell wall at asparagine residues. (O-linked mannan has mannan anchored directly to protein at serine and threonine residues, no chitobiose at the anchor point, no beta linkages at all.) Covalent mannose-mannose bonds, found in side chains of Candida species, e.g. C. guilliermondii have been shown to be of the beta configuration and to be immunogenic (Shibata, N. et al. 1996. JBC 271:9259).
Yeast mannan, the above mentioned carbohydrate portion of yeast cell wall mannoprotein, is a polysaccharide. Upon fractionation to shorter chains, a polysaccharide yields oligosaccharides (shorter chains) and monosaccharides (simple sugars). An empirical mixture of oligosaccharides derived from yeast cell wall mannan is generally referred to as yeast mannan oligosaccharide, or MOS. MOS has been known to animal husbandry as a feed additive promoting weight gain in herds of various livestock, including pigs, cattle, rabbits, and chickens.
Mannan has been known to science as a determinant of immunogenicity. A yeast's mannan determines the immunogenicity for a given yeast, in no doubt the same fashion the high mannose glycosylation found on proteinaceous material generally provokes the immune response. The linkages and mannan structures of different yeast species and the same species grown under different conditions are different. (Shibata, N., supra; Okawa, Y. et al. 2006. Biol. Pharm. Bull. 29:388; Shibata, N. et al. 1996. Arch. Biochem Biophys. 336:49)
For the past several decades, carbohydrate biochemists have labored to elucidate the structure of mannans using mannan immunogenicity as a tool. However, with regard to the disease itself, mannan immunogenicity is a two edged sword: All or part of the structure of a mannan has been elucidated by assaying the immunogenicity of the oligosaccharides that comprise it, and carbohydrate biochemists have also explored the immune response itself. However, it is indeed the immune response to the high mannose glycosylation found on adventitious agents that render bioengineered polypeptides useless or dangerous to patients and cause the bioengineered products to be treated as foreign invaders akin to viruses, toxins, or mere filth.
MOS has been used in animal husbandry as a feed supplement. Several manufacturers produce MOS as an alternative to antibiotics for cattle and poultry feed, among them Bio MOS® (Alltech Biotechnology, Nicolasville, Ky.), CitriStim™ (Archer Daniels Midland Alliance Nutrition, Inc., Quincy, Ill.), and Agrimos® (Lallemand Animal Nutrition, Blagnac, France). A farmer adds this to the animal's feed, at the rate of a few pounds of additive per ton of feed, and the animal puts on weight just as though it were being dosed with the usual prophylactic low levels of antibiotics, maybe even a little better than antibiotic. Bio MOS® and Agrimos® are made from Saccharomyces cerevisiae yeast, common baker's yeast; CitriStim is made from Candida guilliermondii yeast; Species of both Saccharomyces and Candida are quite popular amongst molecular and cell biologists. Agrimos® is obtained by the autolysis of yeast cells at high temperatures and at a controlled pH. After autolysis is completed, cell wall and yeast extracts are separated by centrifugation, and cell wall is spray dried.
The theory behind use of MOS in husbandry is that farm animals suffer from a continual massive colitis. Bacteria—Escherichia coli, mostly—so infect the large intestine of livestock that getting rid of the infecting bacterial pathogens can actually give them a semblance of health. As described by Rozeboom et al. (J. Anim. Sci. 2005. 83:2637), many bacteria possess fimbriae, which are specific surface lectins that bind to the mucosal surface of the intestine to facilitate proliferation of the bacteria (Holland, 1990. Clin. Microb. Rev. 3:345); Stewart et al. 2001. Recent Dev. In Pig Nutrition 3, pgs 51-77, Nottingham Univ. Press, Nottingham, UK) Type I fimbriae specifically bind to glycoproteins that contain mannose. Bio MOS® has been shown to bind, in vitro, to bacterial cells possessing Type I fimbriae—particularly including E. coli (Newman, 1994. Proc. Alltech's 10th Annul. Symp.: Biotechnology in the Feed Industry; Nottingham press, Nottingham, UK; Spring et al., 2000. Poult. Sci. 79:205). Bio MOS® has also been shown to alter immune function (Savage and Zakrzewska, 1996. Poult. Sci. 75:143; David et al., 2004).
Recently, compositions of MOS and methods of use have been disclosed for control of cocccidiosis in poultry (U.S. Ser. No. 07/048,937).